More than 15,000 allogeneic and 30,000 autologous hematopoietic stem cell transplantations (HSCT) are performed annually worldwide (1). Approximately 40% of patients that undergo allogeneic HSCT die from transplantation-related complications, in part due to toxicity of the conditioning regimen to non-hematopoietic tissues (1, 5). A recent approach to decrease conditioning regimen toxicity has been targeted radiotherapy, in which therapeutic doses of radiation are selectively delivered to bone marrow by use antibodies or compounds that indirectly target the bone matrix (5). Targeted radiotherapy can allow for therapy escalation to specific sites such as bone marrow, and provides treatment intensification without toxicity to non-hematological tissues (5). Marrow components can also be indirectly targeted using agents that naturally accumulate within bone re-mineralization sites. Despite advances made using these targeted radiotherapy conditioning regimens, problems still exist. An optimal combination of vector/target antigen and radioisotope has not been achieved, specific transplant protocols have not been determined, and use for the most appropriate diseases has not been pinpointed. To address these issues, we would like to explore a new avenue of myeloablative conditioning therapies that do not utilize radiation, but rather small molecular weight drugs. We propose to identify genes required for survival of only hematopoietic stem cells and committed progenitors, but are not critical for survival of other cell types, by use of RNAi library screening technology. Once identified, these gene products can be used as drug targets for the development of novel myeloablative therapies that will target only cells of the hematopoietic lineage. The rationale is that novel myeloablative therapies that target only those cells of the blood lineage, while leaving other cells of the body unaffected, will greatly reduce the toxicity of conditioning regimens and improve survival rates of patients who must undergo HSCT (5). Development of this technology will provide a publicly available prototype blood cell lineage database outlining reconstructed viability genes and associated pathways, and a set of human FV shRNA libraries, custom services, and RNAi screening technical support will be offered as commercial products and custom services to Cellecta's customers. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify viability genes of hematopoietic stem and progenitor cells in order to find drug targets for new stem cell transplantation and blood cancer therapies. Genes will be identified using RNAi technology, and technology development will allow for production of gene databases, RNAi library products, and the refinement of custom services for our customers.